The discovery of human APOBEC3G (A3G) and related deoxycytidine deaminases as potent intrinsic anti-HIV factors represented an exciting advance in the field of HIV/AIDS research. The later discovery that HIV Vif counters the antiviral effects of A3G by targeting this factor for rapid proteasome-mediated degradation has spawned efforts to create a new class of HIV therapeutics. New insights into the rich biology of A3G have also been gained, including the observation that A3G is expressed in different forms in different cells. Resting CD4 T cells express a low-molecular-mass (LMM) form of A3G that actively restricts the growth of HIV. Conversely, activated CD4 T cells express a high-molecular-mass (HMM) form of A3G that no longer restricts HIV but instead interrupts the retrotransposition of endogenous retroelements like Alu. Intriguingly, Staufen-containing RNA granules form a major component of the HMM A3G complexes. I hypothesize that the biology of A3G is inextricably linked to the inducible formation, dynamic spatial localization, and controlled disassembly of these RNA granules. To test this hypothesis, I propose three specific aims. In Aim 1, I will study the intracellular signals and molecular interactions that govern the formation and disassembly of A3G containing RNA granules and decipher their potential roles in regulating the expression and antiviral activity of human A3G. In Aim 2, I will explore how A3G induces the recruitment of Alu RNA into these RNA granules and in turn how A3G regulates Alu retrotransposition. I will also assess how these interactions modulate the intrinsic antiviral activity of A3G. In Aim 3, I will test the potential role of A3G in controlling Alu-mediated genomic instability and the contribution of such instability to the development of secondary leukemias occurring after genotoxic cancer therapy. For these studies, I will utilize biochemical methods, genome-wide siRNA screening, molecular beacon- and FRET-based imaging approaches in both primary T cells and leukemic cells. The proposed studies promise to provide new insights into the previously unrecognized role of A3G complexes containing RNA granules in controlling retrotransposition of endogenous retroelements. The findings will expand our understanding of A3G biology and could ultimately lead to novel strategies both to protect activated CD4 T cells from HIV infection and to minimize the frequency of cancer therapy-related secondary leukemias.